Atrial fibrillation (AF) is the most common significant arrhythmia, affecting over 2 million Americans. AF is a considerable socioeconomic burden, associated with chronic medication use, nearly one fourth of all strokes in the elderly, and a reduced life expectancy in affected individuals. Most AF is considered to be secondary to other conditions; however, a substantial minority of patients has no obvious cause and are said to have "lone" or primary AF. Clinical and basic investigation suggests that the mechanisms underlying AF are heterogeneous, with multiple factors contributing to the initiation or to the maintenance of the arrhythmia. While the exact nature of any diathesis to AF remains unclear, in some instances such a predisposition is inherited. (Parental AF is a risk factor for the arrhythmia. There are isolated reports of families with AF, a genetic locus has been identified on chromosome 10q22, and recently, a mutation has been described in the KCNQ1 gene. The relationship between such Mendelian families and typical lone AF patients is uncertain, but a simple genetic basis for this condition was felt rare. We initiated a kin-cohort genetic study to dissect the genetic architecture of lone AF in a typical referral population. This strategy allows the discovery of monogenic forms of AF, the evaluation of the causative genes in "sporadic" AF patients, and ultimately the study of gene-environment interactions. We have demonstrated that lone AF has a substantial, unsuspected heritable component. In addition, we have confirmed that lone AF is genetically heterogeneous, and have identified a novel second locus on Chromosome 6q14. We now propose to extend this preliminary work in the following specific aims: 1. To systematically define the clinical genetics of lone AF through: a) Continuing proband-based recruitment of AF families b) Identification of novel subclinical traits or endophenotypes c) Mapping of Mendelian loci using multiplex kindreds 2. To identify the genes responsible for lone AF at the 6q14 locus and other loci. 3. To assess the contribution of the identified gene(s) to AF in a large cohort of probands. Defining the genetic basis of AF will enable early or preclinical diagnosis in at risk individuals, and through better understanding of the basic pathophysiology, the eventual development of novel therapeutic strategies.